Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the results of a recent trial in elderly acute lymphoblastic leukemia (ALL) patients (> or = 60 years). Initial chemotherapy consisted of one 14-day course with single-dose idarubicin plus vincristine-prednisone-L-asparaginase. Idarubicin was preferred to other anthracyclines because of its shorter time to response. Sequential outpatient postremission therapy included single-dose idarubicin plus vincristine-cyclophosphamide-L-asparaginase pulses, cranial irradiation with intrathecal methotrexate-cytarabine, flexible weekly vincristine-cyclophosphamide alternating with cytarabine-teniposide, and two-year standard maintenance with mercaptopurine-methotrexate. Granulocyte colony-stimulating factor (G-CSF) was added to induction and early consolidation courses. Twenty-two patients mainly with high-risk features entered the study: median age was 64 years (60-73), 40% of cases were CD10- B-lineage and T-lineage ALL, 38% of CD10+ B-lineage ALL carried a BCR-ABL rearrangement, while 23% coexpressed myeloid antigen, 86% had L2 morphology, 50% had a blast count greater than 10 x 10(9)/1, 54% had hepato-splenomegaly and lymphadenopathy. The complete remission (CR) rate after induction therapy was 59%. A partial remission was obtained in two cases. There were four early deaths (18%) and three refractory ALL (14%). Median time to response was 21 days. With G-CSF, the median duration of absolute neutropenia was 10.5 days. Flexible postremission therapy was very well tolerated, causing no major toxicity. With a median follow-up of 2.6 years, 3 patients remain alive in first CR (23%), 2 of whom at 21.3 months and 39.6 months, respectively. Median survival of responders was 12 months compared to only 1.2 months for nonresponders (p < 0.001). This moderate-dose idarubicin-containing and G-CSF-supported regimen was associated with a high early remission rate in elderly ALL. Postremission therapy results were modest, though not appreciably different from the general experience in this patient population. Because further escalation of drug intensity appears unjustified, attempts to document and reverse drug resistance patterns and restore a dysregulated apoptosis must be considered.
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PMID:Age-adapted moderate-dose induction and flexible outpatient postremission therapy for elderly patients with acute lymphoblastic leukemia. 881 79

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder that is characterized by splenomegaly and marked elevation of the blood leukocyte count with granulocyte in maturity. Ph chromosome was identified in CML in 1960 and was found to clearly result from reciprocal translocation between chromosome 9 and chromosome 22 (t(q;22)) (q34;q11). CML arises from a single pluripotent hematopoietic stem cell with the Ph chromosome and demonstration of the Ph chromosome in blood or marrow cells establishes and unequivocal diagnosis of CML. The Ph chromosome is recognized as the cytogenetic result of a rearrangement of the ABL gene on chromosome 9 and the BCL gene on chromosome 22, which leads to the creation of a BCR/ABL fusion gene on chromosome 22. Abnormal ABL-related protein with increased tyrosine kinase activity suggested a molecular mechanism of CML. The BCR/ABL fusion gene can be found not only in the chromosome but in interphase nuclei by fluorescence in situ hybridization (FISH). We employed both fluorescence activated cell sorter (FACS) and FISH to study the lineage involvement of individual stem cells and progenitor cells in patients with CML. Evidence of BCR/ABL fusion was found in pluripotent stem cells (CD34+, Thy1+), myeloid cells, B progenitor cells (CD34+, CD19+) and T/NK progenitor cells (CD34+, CD7+, CD5+) but not mature T cells (CD3+) or natural killer cells (CD3-, CD56+). These data suggested that BCR/ABL gene fusion occurs in pluripotent stem cells and that Ph+ T cells and natural killer cells are eliminated during differentiation.
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PMID:[Progress in laboratory medicine in chronic myeloid leukemia]. 991 8

The SCID mouse represents a valuable tool for assessing growth characteristics and drug sensitivity of human leukemic cells. We have examined differences in the engraftment patterns in SCID mice of primary human leukemic cells isolated from children (< 21 years old) with either t(1;19)+/E2A-PBX1+ or t(9;22)+/BCR-ABL+ acute lymphoblastic leukemia. Leukemic cells from 13/24 t(1;19)+/E2A-PBX1+ patients caused overt leukemia in SCID mice. Macroscopic lesions were evident in 6/13 cases, with multiple sites involved in some mice: hepatomegaly,(3) splenomegaly(4), thymic enlargement; liver tumors(1), kidney tumors(1), abdominal tumors(1). Microscopic lesions in SCID mouse organs were present in all 13 cases and involved the bone marrow, brain, heart, gut, liver, kidney, lung, ovary, pancreas, skeletal muscle, spleen, and thymus. Leukemic cells from 5/20 t(9;22)+/BCR-ABL+ patients caused overt leukemia in SCID mice. Notably, macroscopic lesions (splenomegaly; leukemic bones; hepatic tumors) were observed in only 1 case. In all 5 cases, microscopic lesions were found in the mouse bone marrow. Additional microscopic lesions were restricted to skeletal muscle, spleen, and mesentery (1 case) or thymus (1 case). These findings differ markedly from those of t(1;19)+/E2A-PBX1+ leukemic cells due to the lack of involvement of major organs such as liver, pancreas, kidney, skin, or brain. These data illustrate the biological heterogeneity of childhood ALL and suggest that the differential risks associated with t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL ALL might arise from unique engraftment and proliferation capabilities of the respective leukemic cell populations.
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PMID:Distinct in vivo engraftment and growth patterns of t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL+ human leukemia cells in SCID mice. 1003 3

The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.
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PMID:The Italian Consensus Conference on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia. 1019 32

We investigated the significance of p185BCR/ABL expression in patients with chronic myelogenous leukaemia (CML) in relation to disease features, therapy and outcome. Results of Western blot analysis for 1384 patients referred with a diagnosis of CML to our institution from 1989 to 1997 were reviewed. Clinical characteristics, results of cytogenetic analysis and RT-PCR for BCR rearrangement were analysed. Five patients with Ph-positive CML expressing the p185BCR/ABL hybrid protein were identified. By RT-PCR, bone marrow specimens of these patients were confirmed to have an e1a2 junction. The median age at diagnosis of these patients was 55 years (range 43-76). All had elevated white cell counts at diagnosis (median 50 x 109/l, range 11.7-163 x 109/l). Four patients had monocytosis (range 10-16%) with a low neutrophil/monocyte ratio in the peripheral blood (range 3.4-5.7). Patients presented with various stages of the disease (two in chronic-phase CP, two in accelerated-phase AP, and one in blastic-phase BP). The clinical course and therapy of the patients varied, with one patient receiving hydroxyurea only, three patients receiving hydroxyurea followed by interferon-alpha based regimens and bone marrow transplantation. The patient presenting in BP was treated with combination chemotherapy. The clinical outcome of the patients was also varied with one patient alive and in complete remission (with complete cytogenetic remission after transplant) and four patients dead after progression to more advanced stages. We conclude that patients with Ph-positive p185BCR/ABL CML frequently present with monocytosis and a low neutrophil/monocyte ratio in the peripheral blood, aiding the speculation that the presence of the p185BCR/ABL hybrid protein may contribute to a phenotype intermediate between CML and CMML. Of interest, the only other specific clinical feature identified was the absence of splenomegaly in four of five patients. There was no definite association with transformation to lymphoid blast phase.
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PMID:Chronic myelogenous leukaemia with p185(BCR/ABL) expression: characteristics and clinical significance. 1058 63

BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed proliferation, and sensitized cells to apoptotic stimuli. Quantification of activated guanosine triphosphate (GTP)-bound Ras protein and electrophoretic mobility shift assays for AP-1 DNA binding showed that Ras effector pathways are inhibited by SCH66336. However, SCH66336 was more inhibitory than dominant-negative Ras in assays of soft agar colony formation and cell proliferation, suggesting activity against targets other than Ras. Cell cycle analysis of BCR/ABL-BaF3 cells treated with SCH66336 revealed G2/M blockade, consistent with recent reports that centromeric proteins that regulate the G2/M checkpoint are critical farnesylated targets of FTI action. Mice injected intravenously with BCR/ABL-BaF3 cells developed acute leukemia and died within 4 weeks with massive splenomegaly, elevated white blood cell counts, and anemia. In contrast, nearly all mice treated with SCH66336 survived and have remained disease-free for more than a year. Furthermore, SCH66336 selectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct from that of ABL tyrosine kinase inhibition, FTI SCH66336 shows promise for the treatment of BCR/ABL-induced leukemia.
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PMID:Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. 1122 87

There are two major forms of the BCR/ABL fusion gene, involving ABL exon 2, but including different exons of BCR gene. The transcripts b2a2 or b3a2 code for a p210 protein. Another fusion gene leads to the expression of an e1a2 transcript, which codes for a p190 protein. Another, less common fusion gene is c3a2[e19a2], which encodes a p230 protein. The incidence of one or the other rearrangement in chronic myeloid leukaemia (CML) patients varies in different reported series. This study was designed to determine the frequency of coexpresion of the p210, p190 and p230 transcripts in 250 Mexican patients with CML. We performed nested and multiplex reverse transcriptase polymerase chain reaction (RT-PCR) on bone marrow samples from adult patients and found that all cases were positive for some type of BCR/ABL rearrangement. In 226 (90.4%) patients it was p210, while the remaining 9.6% showed coexpression or one of the transcripts of p190/p210/p230. In 7% of patients with p210 expression there are both isoforms (b3a2/b2a2), presumably the result of alternative splicing. The rate of coexpression of the p190/p210 transcripts was 5%, which is much lower than in other reports. This may be due to the technical factors. These patients had high platelet counts, marked splenomegaly and chromosomal abnormalities in addition to Ph'. Other types of coexpression seen were p210/p230 and p190/p210/p230, in patients with high-risk clinical factors. Our study confirms the occurrence of coexpression of different BCR/ABL transcripts, although the rate (9.6%) was much lower than has been reported in other populations. This may reflect either the sensitivity of the detection techniques used or the possibility of genetic differences between the populations studied. Coexpression may be due to alternative splicing or to phenotypic variation, with clinical courses different from classical CML.
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PMID:BCR/ABL p210, p190 and p230 fusion genes in 250 Mexican patients with chronic myeloid leukaemia (CML). 1206 77

We report a 39-year-old female patient who underwent HLA-identical sibling allogeneic BMT for CML in accelerated phase. Severe pancytopenia refractory to G-CSF associated with progressive splenomegaly and RBC/platelet transfusion dependency were present from day +60 after BMT. MRD assessed by FISH and RT-PCR multiplex for BCR-ABL rearrangement was negative, and complete chimerism was documented by VNTR on days +100, +180, +360 and 2 years after BMT. Splenectomy was performed on day +225 and pancytopenia resolved but chronic extensive graft-versus-host disease developed, with hepatic cholestasis, diffuse scleroderma and sicca-like syndrome. She was sequentially and progressively treated with different immunosuppressive therapy combinations with no clear benefit. On day +940, she presented with infection over the previously present ulcers on both limbs, which culminated in septic shock and death on day +1041. We conclude that, although splenectomy may reverse poor graft function after allogeneic BMT, hyposplenism may trigger or worsen chronic extensive GVHD leading to increased morbidity and mortality.
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PMID:Refractory chronic GVHD emerging after splenectomy in a marrow transplant recipient with accelerated phase CML. 1285 7

We describe a patient with chronic myelogenous leukemia (CML), in whom the DNA breakpoint in the BCR-ABL fusion gene was determined to result in a rare e13a3 (b2a3) transcript. The breakpoint in BCR was intron 13, which was 30 bp downstream from exon 13, and the breakpoint in ABL was intron 2, and was 46 bp downstream from exon a2. This case conforms to the mechanism of DNA breakage occurring within ABL intron 2, but not at 5' to ABL exon a2. With our review of this case and the literature, it seems that CML with the BCR-a3 fusion product is associated with a low proportion of circulating immature cells, mild or lack of splenomegaly, slow progressiveness, rather resistance to IFN-alpha, and good response to imatinib mesylate. This is the first report of BCR-a3-type CML in which the exact DNA breakpoint was identified and located between exons a2 and a3 of the ABL gene.
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PMID:Chronic myelogenous leukemia with e13a3 (b2a3) type of BCR-ABL transcript having a DNA breakpoint between ABL exons a2 and a3. 1463 8

We reviewed 261 patients with chronicphase chronic myelogenous leukemia (CML) after interferon-alpha (IFN-alpha) failure treated with imatinib mesylate 400 mg daily. With a median follow-up time of 45 months, the major cytogenetic response rate was 73% and the complete cytogenetic response rate 63%. The estimated 4-year survival rate was 86%. Multivariate analysis for survival identified hematologic resistance to IFN-alpha (P =.01), splenomegaly (P =.03), and lack of any cytogenetic response after 3 months of therapy (P =.01) to have independent poor prognostic significance. Patients could be divided into good (no adverse factors), intermediate (1 adverse factor), and poor-risk groups (2 or 3 adverse factors; 12% of patients) with estimated 4-year survival rates of 96%, 86%, and 49%, respectively (P <.00001). The 4-year cumulative major molecular response (quantitative reverse transcriptase-polymerase chain reaction [Q-PCR] = BCR-ABL/ABL less than 0.05%) rate was 43% and complete molecular response rate (BCR-ABL undetectable) 26%. Compared with a historical group of 251 similar patients treated with nonimatinib therapies, imatinib mesylate was associated with a better 4-year survival rate (86% versus 43%; P <.0001); the survival advantage was confirmed by multivariate analysis (hazard ratio, 0.19; P <.0001).
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PMID:Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. 1519 56


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